Increasing evidence suggests that mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD), but the earliest neuropathological changes that signal the onset of AD, as well as the underlying mechanisms of AD, remain enigmatic. Although the brains of patients with fully evolved AD are characterized by senile plaques (SPs) formed by fibrillar amyloid beta (AB) and neurofibrillary tangles (NFTs) formed by paired helical filaments (PHFs) assembled from hyperphosphorylated tau (PHFtau), greater than 50% of sporadic and familial AD, as well as elderly Down's syndrome brains, also show accumulations of Lewy bodies (LBs). Indeed, similar to Parkinson's disease (PD) as well as other synucleinopathies and the LB variant of AD, the major building block proteins of filamentous LBs in sporadic and hereditary AD are abnormal alpha-synuclein (AS). While the mechanisms that convert normal A-beta, tau and AS into insoluble filaments that aggregate into SPs, NFTs and LBs, respectively, are poorly understood, nitrative/oxidative damage has been implicated in the pathogenesis of AD, and the brain is particularly vulnerable to nitrative or oxidative damage. Thus, it is timely to examine the brains and body fluids of subjects with early AD, MCI and no cognitive impairment (NCI) for increased lipid peroxidation (LPO) by measuring species of isoprostanes (iPs) that are specific and sensitive markers of LPO, and we have shown the utility of measuring a major iP known as 8,12-iso-iPF2v-VI (iPF2v-VI) because it is increased in AD brains as well as in urine, plasma and cerebrospinal fluid (CSF) of patients with AD thereby raising the possibility that it may be a useful biomarker for the onset MCI and progression to AD. In addition, Project 1 will test the hypothesis that nitrative/oxidative damage is an early harbinger of MCI that alters the biophysical properties of normal AB, tau and AS thereby converting them into insoluble filaments of SPs, NFTs and LBs, respectively. These studies will be conducted on brains and body fluids from well characterized elderly members of a religious orders study (ROS) cohort with NCI, MCI or AD. Completion of this project will to lead to new insights into mechanisms of MCI and AD as well as identify potential therapeutic targets for treating these disorders.